Note: Descriptions are shown in the official language in which they were submitted.
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ORAL COMPOSITIONS OF ABT-263 FOR TREATING CANCER
FIELD OF THE INVENTION
This invention pertains to methods of treating cancer using N-(4-(4-((2-(4-
chlorophenyl)-5,5 -dimethyl- l -cyclohex- l -en- l -yl)methyl)pip erazin-1-
yl)benzoyl)-4-(((1 R)-
3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3 -
((trifluoromethyl)sulfonyl)benzenesulfonamide.
BACKGROUND OF THE INVENTION
Anti-apoptotic Bcl-2 family protein members are associated with a number of
diseases and are therefore under investigation as potential therapeutic drug
targets. These
important targets for interventional therapy include, for example, the Bcl-2
family of
proteins Bcl-2, Bcl-XL and Bcl-w. While this art teaches inhibitors having
binding to the
target protein, this is only one of many parameters that must be considered as
a compound is
investigated for further or continued drug development. As part of this
development, it is
highly desirable to have compounds that are orally efficacious in mammals and
have
tolerable side-effects profiles, the nature of which are preferably determined
by
administering to mammals and determining the side-effects and severity
thereof.
Accordingly, there is an existing need in the therapeutic arts for efficacious
cancer
chemotherapeutics with tolerable side effects profiles.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a graph showing mean ABT-263 plasma concentrations during dosing
at
315 mg.
Figure 2 is a graph showing dose proportionality under fasting and non-fasting
conditions.
Figure 3 illustrates effect of ABT-263 on platelets at different doses over
several
dosing cycles.
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Figure 4 illustrates the timing and dose-dependency of effect of ABT-263 on
platelets.
SUMMARY OF THE INVENTION
The present invention relates to a composition for oral administration
comprising N -
(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l -cyclohex- l -en-l-
yl)methyl)piperazin-1-
yl)benzoyl)-4-(((1 R)-3-(morpholin-4-yl)-1-
((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide , Phosal 53 Medium Chain
Triglyceride
and dehydrated ethanol.
DETAILED DESCRIPTION OF THE INVENTION
The compound N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-1-
yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3 -(morpholin-4-yl)- l -
((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide is
also referred to herein as ABT-263.
ABT-263 is a small molecule Bcl-2 family protein inhibitor that binds with
high
affinity (Ki < 1 nM) to multiple anti-apoptotic Bcl-2 family proteins
including Bcl-XL, Bel-
2, Bcl-w, and Bcl-B. By binding to these proteins, ABT-263 releases the pro-
apoptotic
family members, thus resulting in cell death by apoptosis. ABT-263 displays
potent
mechanism-based cytotoxicity (EC50 <_ 1 M) against human tumor cell lines
derived from
small cell lung carcinomas and lymphoid malignancies. ABT-263 also displays
potent single
agent activity against 10 of 22 cell lines consisting of multiple leukemia and
lymphoma
types spanning both B-cell and T-cell malignancies.
Metabolites of ABT-263, produced by in vitro or in vivo metabolic processes,
may also have
utility for treating cancer.
Certain precursor compounds of ABT-263 may be metabolized in vitro or in vivo
to
form ABT-263 and may thereby also have utility for treating cancer.
Therapeutically effective amounts of a ABT-263 depend on recipient of
treatment,
disease treated and severity thereof, composition comprising it, time of
administration, route
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of administration, duration of treatment, potency, rate of clearance and
whether or not
another drug is co-administered.
ABT-263 may be administered with or without an excipient. Excipients include,
for
example, encapsulators and additives such as absorption accelerators,
antioxidants, binders,
buffers, coating agents, coloring agents, diluents, disintegrating agents,
emulsifiers,
extenders, fillers, flavoring agents, humectants, lubricants, perfumes,
preservatives,
propellants, releasing agents, sterilizing agents, sweeteners, solubilizers,
wetting agents and
mixtures thereof.
In two flank models of diffuse large B-cell lymphoma (DoHH-2 and WSU-DLCL2),
significant monotherapy activity was noted when ABT-263 was administered at a
dose of
100 mg/kg/day given p.o., q.d. x 17 days. Both of these tumors are known to
express high
levels of Bcl-2 due to the t(14;18) translocation. The WSU-DLCL2 line was
isolated from a
patient whose disease progressed following chemotherapy, radiation therapy and
bone
marrow transplantation and is recognized as a model of therapy-resistant
lymphoma.
The pharmacokinetic profile of ABT-263 was evaluated in multiple animal models
including CD-1 mouse, Sprague-Dawley rat, beagle dog and cynomolgus monkey.
The
nonclinical pharmacokinetic profile of ABT-263 is characterized by very low
plasma
clearance and low volumes of distribution in all species studied, with
terminal half-lives in
the range of 4.6 to 8.4 hours. The oral bioavailability of the compound is
formulation
dependent, with values of 30% to 50% obtained from prototype solid dispersion
and
lipid-based formulations in dog. In rat, (14C) ABT-263 is slowly absorbed,
with clearance of
the metabolites primarily in the bile. Elimination of total radioactivity is
rapid, with 90% of
the dose recovered within 24-hours post-dose. Parent drug is the major
component in
systemic circulation.
Based on preclinical evidence, potential treatment-related side effects may
include
drug interactions, lymphopenia, testicular effects, and thrombocytopenia. At
the expected
biologically effective plasma concentration in humans of 6.7 .iM, ABT-263 is
likely to
inhibit the metabolism of drugs that are substrates for CYP2C8 and CYP2C9.
Simulation of
350 mg q.d. dosing in humans describes an AUC of 92 .ig.hr/mL at steady state,
with a CmaX
of '6.5 .ig/mL. Under these conditions, platelet values are expected to be '25
K/.iL at steady
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state. At the lower end of the predicted efficacious range, an AUC of 53
.ig.hr/mL (predicted
200 mg q.d. dosing in humans) is expected to be attainable while still
maintaining platelet
values above 50 K/.iL at steady state.
Toxicology
The potential genetic toxicity of ABT-263 was evaluated in the
Salmonella-Escherichia coli bacterial mutation assay, chromosomal aberration
assay in
cultured human peripheral blood lymphocytes, and in an in vivo rat
micronucleus assay.
ABT-263 was not mutagenic in the Ames assay, with or without metabolic
activation, did
not induce chromosome aberrations in human lymphocytes in vitro, with or
without
metabolic activation, and was not clastogenic in the in vivo rat micronucleus
assay. These
findings suggest that ABT-263 is not genotoxic.
In rats, ABT-263 -related toxicities included mild to marked decreases in
platelets,
minimal to moderate decreases in lymphocytes, and minimal to mild increases in
liver
enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
alkaline
phosphatase). Although rats had mild to marked decreases in platelets
following a single
administration of ABT-263, there was a partial recovery of platelets during
repeated
administration that likely represents the normal physiologic response to
decreases in
platelets. Platelet levels returned to normal after cessation of ABT-263
treatment.
Additionally, the ABT-263-related microscopic changes observed in rats
included single-
cell necrosis in multiple epithelial cell types (hepatocytes, nasal
epithelium, parotid salivary
gland, pancreas, seminal vesicles, and ureters), depletion of spermatogonia
and
spermatocytes, and a decrease in cortexical and medullary lymphocytes in the
thymus
consistent with thymic atrophy. Based on data from the 4-week rat toxicity
study, a
no-observed-adverse-effect-level (NOAEL) was not reached because of effects on
platelets
at all doses; however, the 10 mg /kg/day dose was considered a tolerated dose.
In dogs, toxicities included a marked decrease in platelets and a mild
decrease in
lymphocytes. In a 2-week toxicity study, dogs with low platelet counts (< 50
K/gL) tended
to have a prolonged bleeding time compared to either control dogs or their own
baseline
values. In a 4-week toxicity study in dogs, there was a marked decrease in
circulating
platelet counts that then increased during the treatment period at some doses.
This effect on
platelets was fully reversible in less than 7 days after ABT-263 treatment
ended. Target
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organs in the dog included lymphoid tissues (spleen, Peyer's patch, lymph
nodes, and
thymus (a 2-week study)), male reproductive tissues (testes and epididymides),
and
pancreas. The microscopic changes observed in these target organs included
decreased size
of follicles, cortex, and/or germinal centers in lymphoid tissue; decreased
cellularity in
mantle zone, germinal centers, and/or interfollicular areas of lymphoid
tissue;
spermatogonia, spermatocyte and/or spermatid (round and elongated) depletion;
and
pancreatic acinar cell single cell necrosis. With the exception of pancreatic
acinar cell single
cell necrosis, these microscopic changes were also noted following a 4-week
dose-free
recovery period. The NOAEL following 4 weeks of administration of ABT-263 to
dogs was
1 mg/kg/day.
The primary toxicological finding of a decrease in circulating platelets in
mouse, rat
and dog is concentration dependent and is expected to be the dose limiting
toxicity for ABT-
263 in humans. Thrombocytopenia was seen after administration of a single dose
and is
present at the time of Cmax. After a single dose, the platelet counts return
to normal values
over approximately one week with an accompanying increase in mean platelet
volume.
Although there were marked decreases in platelets, this toxicity was tolerated
for up to 28
days in both rat and dog.
Non-Hodgkin's Lymphoma (NHL)
NHL is the sixth leading type of new cancers in the U.S. and occurs primarily
in
patients 60-70 years of age. NHL is a family of related diseases, which are
classified on the
basis of multiple characteristics including clinical attributes and histology.
One method of
classification places the different histologic subtypes into two major
categories based on
natural history of the disease: indolent and aggressive. In general, indolent
subtypes grow
slowly and are generally incurable whereas aggressive subtypes grow rapidly
and are
potentially curable. Follicular lymphomas are the most common indolent
subtype, and
diffuse large cell lymphomas constitute the most common aggressive subtype.
The
oncoprotein Bcl-2 was originally described in Non-Hodgkin's B Cell Lymphoma.
Treatment of follicular lymphoma typically consists of biologically-based or
combination
chemotherapy. Therapy with rituximab, cyclophosphamide, doxorubicin,
vincristine, and
prednisone (R-CHOP) is routinely used, as is rituximab, cyclophosphamide,
vincristine, and
prednisone (RCVP). Single-agent rituximab (targeting the uniformly expressed
CD20) and
fludarabine are also used; rituximab (Rituxan) added to chemotherapy regimens
has shown
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improved response rates and increased progression-free survival (PFS).
Radioimmunotherapy agents and stem cell transplants may be used to treat
refractory
disease. However, since cure is rare with standard therapy, current guidelines
recommend
that patients be treated in the context of a clinical trial, even in first
line settings.
First line treatment of patients with aggressive large B-cell lymphoma
typically consists of
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-
CHOP), or
etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-
EPOCH-R).
High dose chemotherapy and stem cell transplant may also be used to treat
relapsed or
refractory disease. Currently, there is not an approved treatment regimen that
produces a
cure and current guidelines recommend that patients be treated in the context
of a clinical
trial, even in the first line setting.
Most lymphomas respond initially to any one of these therapies, but tumors
typically
recur and eventually become refractory. As the number of regimens patients
receive
increases, the more chemotherapy resistant the disease becomes. Average
response to first
line therapy is approximately 75%, 60% to second line, 50% to third line, and -
35-40% to
fourth line. Response rates with a single-agent in the multiple relapsed
setting approaching
20% are considered positive and warrant further study.
Current chemotherapeutic agents elicit their antitumor response by inducing
apoptosis
through a variety of mechanisms. However, many tumors ultimately become
resistant to
these agents. Bcl-2 and Bcl-XL have been shown to confer chemotherapy
resistance in both
short-term survival assays in vitro and more recently, in vivo. This suggests
that therapies
aimed at suppressing the function of Bcl-2 and Bcl-XL might successfully
overcome this
chemotherapy resistance.
Lymphoid malignancies are an attractive target for ABT-263 due to Bcl-2
overexpression in a high percentage of patients. Thus, a Phase 1/2a study
evaluating the
safety, pharmacokinetics, and preliminary efficacy of the orally administered
Bcl-2 family
protein inhibitor, ABT-263, in subjects with relapsed or refractory lymphoid
malignancies
was initiated. The Phase 1 is the dose escalation portion of the study and the
Phase 2a is the
safety expansion portion of the study at the recommended Phase 2 dose.
The study consisted of two distinct portions. The Phase 1 portion of the study
evaluated the pharmacokinetic profile and safety of ABT-263 in approximately
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30-40 subjects following dose escalation with the objective of defining the
dose limiting
toxicity (DLT) and the maximum tolerated dose (MTD). The effect of food on
bioavailability was also assessed in Phase 1. Subjects were enrolled at
approximately eight
research sites for the Phase 1 portion of the study. The Phase 2a portion of
the study
evaluated ABT-263 at the defined recommended Phase 2 dose (RPTD) in
approximately 40
subjects with follicular lymphoma and 20 subjects with aggressive large B-cell
lymphoma to
obtain additional safety information and a preliminary assessment of efficacy
as defined in
Section. Arm A had approximately 20 subjects with relapsed or refractory
follicular
lymphoma. Arm B had approximately 20 subjects with follicular lymphoma that
have
become resistant to rituximab (progressed within 6 months of a previous
rituximab
treatment). Arm C had approximately 20 subjects with aggressive large B-cell
lymphoma.
Subjects in the Phase 2a portion of the study was enrolled at approximately
twenty research
sites.
Phase 1
Inclusion Criteria
A subject was eligible for study participation if he/she: was about 18 years
old; had a
histologically documented diagnosis of a lymphoid malignancy as defined in the
World
Health Organization (WHO) classification scheme; had received at least 1 prior
chemotherapy treatment regimen for a lymphoid malignancy and their disease is
refractory
or the subject has experienced progressive disease following the treatment;
if, over the age
of 70, had documented brain imaging (MRI or CT) negative for subdural or
epidural
hematoma within 28 days prior to the first dose of study drug; had an Eastern
Cooperative
Oncology Group (ECOG) performance score of about 1; if receiving selective
serotonin
reuptake inhibitor anti-depressants (e.g., Prozac), must have been receiving a
stable dose for
at least 21 days prior to the first dose of study drug; had adequate bone
marrow, renal and
hepatic function per local laboratory reference range as follows: bone marrow:
absolute
neutrophil count (ANC) of about 1,000/il; platelets of about 100,000/mm3; and
hemoglobin
of about 9.0 g/dL; renal function: serum creatinine of about 2.0 mg/dL or
calculated
creatinine clearance of about 50; hepatic function and enzymes: AST and ALT of
bout 3.0
xthe upper normal limit (ULN) of institution's normal range; Bilirubin - 1.5 x
ULN.
Subjects with Gilbert's Syndrome may have a Bilirubin > 1.5 x ULN;
coagulation: aPTT, PT
not to exceed 1.2 x ULN. Female subjects had to be surgically sterile,
postmenopausal for at
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least one year or have negative results for a pregnancy test and non-
vasectomized male
subjects must have practiced birth control.
ABT-263 Administration
For the first cycle of Phase 1, ABT-263 was administered on Day-3 (single day
of
dosing 3 days prior to Day 1 of Cycle 1) and Days 1 through 14 followed by
seven days off
drug to complete a 24-day cycle (Cycle 1 only). All subjects received ABT-263
under
fasting conditions on Day-3 and under non-fasting conditions (after a standard
breakfast) on
Day 1 to study the effect of food on the ABT-263 pharmacokinetic profile.
There was no
drug administered for the 72 hours following the first dose of the first cycle
(Day-3) in order
to assess the single-dose pharmacokinetics and toxicity. ABT-263 was
administered for 14
consecutive days followed by seven days off drug (21-day cycle) for all
subsequent cycles.
Except for Days-3 and 1 of the first cycle, subjects was instructed to self-
administer ABT-
263 orally once daily (QD) at approximately 30 minutes after breakfast on
dosing days in
Phase 1. The effect of food on pharmacokinetics was evaluated and changes was
initiated if
fasting conditions are superior.
ABT-263 Dosing
Dosing with ABT-263 began at 10 mg and escalate to MTD with a minimum of three
subjects in each cohort. The study drug dose was escalated with a doubling of
dose until one
grade 3 or two grade 2 toxicities occured, after which dose escalation was
continued in
standard 25%-40% increments. This range allows for accurate dispensing of the
oral dose
from the required syringe. Platelet levels after each cohort were reviewed by
the investigator
and the Medical Monitor and informed all dose escalation decisions. Predicted
efficacious
concentrations of ABT-263 were expected to occur in the range of 200 mg to 350
mg.
The first subject in each dose cohort must complete two weeks of dosing before
additional
subjects may be enrolled. This provision might be discontinued as safety
information was
reviewed from early cohorts by the investigator and the Medical Monitor and it
is
determined that dose escalation can proceed safely without a stagger in
subject enrollment.
Escalation of ABT-263 to the next dose level will proceed if all assigned
subjects in a given
cohort complete the cycle without experiencing a dose-limiting toxicity (DLT).
If one
subject within any dose level experiences a DLT, a total of six subjects was
enrolled at that
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dose level. If > 2 of 6 subjects experience a DLT, the previous dose was
considered for
MTD or dose de-escalation may occur as follows:
If two or more subjects in a cohort experiences a DLT at any dose level after
doubling of the previous dose, the next dose level was reduced by 20-25% from
the current
dose. If less than two of six subjects experience a DLT at this reduced level,
this dose was
declared MTD. An additional 20-25% dose reduction may be needed if two or more
subjects
in a cohort still experiences a DLT. If the 20-25% dose reduction tested is
deemed well
tolerated (0/3 DLTs) then a 10-15% increase may be initiated at the discretion
of the sponsor
and the investigator(s).
MTD were defined at the highest dose level at which less than 2 of 6 subjects
experience a DLT.
TABLE 2
Dose Escalation Guidelines
Number of Subjects with DLT Dose Escalation
0 of 3 Begin enrollment in the next dose level
1 of 3a Enroll a total of six subjects in current dose level
1 of 6a Begin enrollment in the next dose level
> 2 of 6 with DLT Previous dose determined as MTD or dose de-
a. Revert to standard 25%-40% dose escalation
Subject assessments for safety and clinical progression continued weekly
through the
first 2 cycles. Subsequently, subject assessments for safety and clinical
progression was
performed once every cycle (every three weeks).
Intra-subject Dose Escalation and Continuous Dosing in Phase 1
To collect information on an alternative dosing schedule with ABT-263,
subjects
might change to a continuous dosing schedule for the 21-day cycle at their
current assigned
dose level. Subjects needed to complete 2 cycles at the original dosing
schedule of 14 days
of dosing followed by 7 days off drug. Subjects may be deemed eligible for the
continuous
dosing schedule if they tolerated the first 2 cycles of drug and the Medical
Monitor agrees
on their eligibility.
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Once a subject changes to a continuous dosing schedule, the subject remained
on that
schedule (even if the subject later dose escalates) unless a change is
warranted due to
toxicity, based on the judgment of the investigator.
In addition, to maximize the collection of information at relevant doses and
to
minimize the exposure of individuals to sub-optimal doses, subjects may
progressively
escalate their current dose to the highest dose level tolerated through 2
cycles of ABT-263
administration. Individuals will need to complete at least two cycles at their
originally
assigned dose level, as well as subsequent dose levels, prior to any dose
escalation.
All intra-subject dose escalation and continuous dosing decisions was based on
the
judgment of the investigator in coordination with the Abbott Medical Monitor.
Once the
MTD is declared and the RPTD is determined, subjects who remain on study and
continue
to tolerate the drug may escalate to the dose level determined to be the RPTD
or the dose
level below the RPTD under a continuous dosing schedule. The RPTD was defined
by
observed DLTs and determination of MTD.
Subject assessments for safety (physical examination, vitals signs, chemistry,
hematology, urinalysis and adverse event assessment) were performed weekly
during the
first cycle at the new escalated dose or new dose schedule and then resumed to
once every
cycle. All other procedures (platelet count, echocardiogram and ECG) were
performed
according to the schedule of assessments.
Transition of ABT-263 Dosing from Phase 1 Part to Phase 2a Part
Once the MTD is reached, enrollment into the Phase 1 portion of the study
ended
and a safety analysis was performed. The results of the safety analysis as
well as the
recommended Phase 2 dose was communicated to all participating research sites
prior to the
start of enrollment in the Phase 2a portion of the study. Phase 1 subjects are
not eligible for
enrollment in the Phase 2a portion of the study but may continue receiving ABT-
263 for up
to one year provided they continue to tolerate the drug, have no evidence of
disease
progression, and do not meet any of the criteria for subject discontinuation.
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Phase 2a
Inclusion Criteria
A subject was eligible for study participation if he/she: was > 18 years of
age;
had a histologically documented diagnosis of follicular lymphoma (subjects
enrolling in
Arm C must had a histologically documented diagnosis of aggressive large B-
cell
lymphoma); had a measurable disease by International Working Group (IWG)
Criteria for
Tumor Response; had met one the following criteria: follicular lymphoma (Arm
A) having
received at least one and no more than four prior conventional chemotherapy
regimens and
their disease was refractory or the subject had experienced progressive
disease following
treatment; follicular lymphoma (Arm B) that had become resistant to rituximab
(i.e.
progressed within 6 months of a previous rituximab treatment); aggressive
large B-cell
lymphoma (Arm C) after having received at least one and no more than four
prior
conventional chemotherapy regimens and their disease is refractory or the
subject has
experienced progressive disease following the treatment; if clinically
indicated (e.g.,
subjects over the age of 70), had documented brain imaging (MRI or CT)
negative for
subdural or epidural hematoma within 28 days prior to the first dose of study
drug; had
archived diagnostic tissue available for assessment of Bcl-2 family protein
expression; had
one of the following available for pharmacodynamic analyses:core needle biopsy
of
malignant lymph node obtained at screening; bone marrow aspirate or core
obtained at
screening, positive for lymphoma; archived tumor tissue with no intervening
treatment since
the biopsy (e.g., from debulking, tissue obtained at relapse or bone marrow
sample); had an
Eastern Cooperative Oncology Group performance score of about 1; for subjects
receiving
Selective Serotonin Reuptake Inhibitor (SSRI) anti-depressants (e.g., Prozac)
must have had
a stable dose for at least 21 days prior to the first dose of study drug; had
adequate bone
marrow, renal and hepatic function per local laboratory reference range as
follows: bone
marrow: absolute neutrophil count (ANC) of about 1,000/il; platelets of about
100,000/mm3;
hemoglobin of about 9.0 g/dL;renal function: serum creatinine of about 2.0
mg/dL or
calculated creatinine clearance of about 50;hepatic function and enzymes: AST
and ALT of
about 3.0 x the upper normal limit (ULN) of institution's normal range;
bilirubin of about 1.5
x ULN. Subjects with Gilbert's Syndrome may have a Bilirubin > 1.5 x ULN;
coagulation:
aPTT, PT not to exceed 1.2 x ULN. Female subjects had to be surgically
sterile,
postmenopausal for at least one year or have negative results for a pregnancy
test and
non-vasectomized male subjects must have practiced birth control.
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ABT-263 Dosing
ABT-263 was administered for 14 consecutive days followed by 7 days off drug
for
the Phase 2a portion of the study. Arm A will evaluate ABT-263 in subjects
with relapsed or
refractory follicular lymphoma, Arm B will evaluate ABT-263 in subjects with
rituximab
resistant follicular lymphoma, and Arm C will evaluate ABT-263 in subjects
with aggressive
large B-cell lymphoma. All subjects will self-administer ABT-263 at
approximately 30
minutes after breakfast, unless results from the Phase 1 food effect study
indicate fasting
conditions are superior. If, during Phase 2a, dose-limiting toxicities were
observed at a
frequency higher than the definition of MTD (> 33%), the investigator and
reviewed the
data and determined whether dosing should continue or a new, lower recommended
Phase 2
dose was defined.
Physical Examination
A physical examination (including weight) were performed at Screening, Cycle 1
Day -3 (Phase 1) or Cycle 1 Day 1 (Phase 2a), Day 1 of each subsequent cycle
(or within 72
hours prior), at Final Visit and at the Safety Follow-up Visit. A symptom-
directed physical
examination were performed weekly through the first 2 cycles and when
necessary. Height
were measured only at Screening. The physical examination performed at
Screening will
serve as the baseline physical examination for clinical assessment. Any
clinically significant
physical examination findings after dosing were recorded as adverse events.
Vital Signs
Body temperature (oral), blood pressure and pulse were measured at Screening,
Cycle 1 Day
-3 (Phase 1) or Cycle 1 Day 1 (Phase 2a), weekly through the first 2 cycles,
Day 1 of each
subsequent cycle (or within 72 hours prior), at Final Visit and at the Safety
Follow-up Visit.
The vital sign measurements at Screening will serve as the baseline
measurements for
clinical assessment.
Blood pressure and pulse rate were measured 30 to 60 minutes after study drug
administration and after the subject has been sitting for at least 5 minutes.
Platelet Count
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Platelet counts were performed stat and assessed by the investigator or
subinvestigator prior
to study drug administration as follows:
Phase 1:
Screening
Cycle 1:
= Day -3 through Day 2
o Platelet counts were drawn at all of the pharmacokinetic sampling time
points
on Days -3 through 2.
= Days 3, 4, 5,6and8
o If platelet count is below 50,000/mm3 on Day 8, platelet counts were drawn
daily on Day 9 and Day 10.
= Day 11
o If platelet count is below 50,000/mm3 on Day 11, platelet counts were drawn
daily on Day 12 and Day 13.
= Day 14
o Platelet counts were drawn at all of the pharmacokinetic sampling timepoints
on Day 14, as indicated in Table 5.
= Day 16
= As needed
Subsequent Cycles:
= Dayl,3,5,8andl6
= As needed
Final Visit and Safety Follow-up Visit
21/21 Day Continuous Dosing Schedule-Phase lb
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Screening
Lead In Period
Lead-In Days 1, 2, 3, 5 and 7
If the lead-in period extends beyond 7 days, platelet counts will be drawn
prior to
dosing on each additional lead-in day (Lead-in Days 8-14).
Cycle 1:
= Day l
o Platelet counts will be drawn at all of the pharmacokinetic sampling time
points on Day 1
= Days 2, 3, 5 and 8
= Day 14
o Platelet counts will be drawn at all of the pharmacokinetic sampling time
points on Day 1
= Day 16
= As needed
Subsequent Cycles:
= Weekly
o If a platelet count on any given day is less than 50,000/mm3, additional
platelet counts should be performed every day or at the discretion of the
investigator.
o As needed
Final Visit and Safety Follow-up Visit
Phase 2a:
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Screening Cycle 1:
= Days 1, 2, 3, 5, 8, 14 and 16
= As needed
Subsequent Cycles
o Weekly and as needed
o If the investigator and Abbott Medical Monitor jointly agree that platelet
counts through Cycle 4 have been stable, then the frequency of platelet counts
in Cycle 5 and beyond may be decreased to Day 1 of each Cycle and as
needed.
Final Visit and Safety Follow-up Visit
Phase la, Phase lb and Phase 2a
If a platelet count on any given day is less than 50,000/mm3, additional
platelet
counts should be performed very day or at the discretion of the investigator.
If a platelet transfusion is necessary, a post-transfusion platelet count
should be
obtained within 10-60 minutes of the transfusion being completed.
The platelet count measurement obtained on Cycle 1 Day -3 (pre-dose) will
serve as the
baseline for clinical assessment in the Phase 1 a portion of the study.
The platelet count measurement obtained on Lead-In Day 1 (pre-dose) will serve
as the
baseline for clinical assessment in the Phase lb portion of the study.
The platelet count measurement obtained on Cycle 1 Day 1 (pre-dose) will serve
as the
baseline for clinical assessment in the Phase 2a portion of the study.
Platelet count from an automated reading is less than 25,000/mm3 should be
confirmed the
same day by manual reading and a separate peripheral draw. Additional platelet
counts will
be obtained from a subject if ABT-263 is either held or interrupted per the
management
guidelines.
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All platelet count measurements obtained through Cycle 4 in Phase la and Phase
lb will be
faxed to the Oncology Group Safety Desk within 24 hours via the contact
information
provided in Section 6.5.
The platelet count schedule of assessment may be modified as information is
obtained
regarding the expected decrease in platelets in response to study drug
administration. This
will be based upon discussion between the investigator and the Abbott Medical
Monitor.
The lymphocyte enumeration results from Screening will serve as the baseline
for clinical
assessment.
Lymphocyte enumeration to identify B and T cell lymphocyte subpopulations were
performed at Screening, Cycle 1 Day 14, after Cycle 4 and at the Final Visit
for each
subject. All lymphocyte enumeration results obtained in Phase la and Phase lb
portions of
the study will be faxed to the Oncology Group Safety Desk as soon as they are
available via
the contact information provided in Section 6.5.
Status
The ECOG performance status were assessed at Screening, Cycle 1 Day -3 (Phase
la) or
Cycle 1 Day 1 (Phase lb and Phase 2a), weekly through the first two cycles,
Day 1 of each
subsequent cycle (or within 72 hours prior), at the Final Visit and at the
Safety Follow-up
Visit as follows:
Grade Description
0 Fully active, able to carry on all pre-disease performance without
restriction.
1 Restricted in physically strenuous activity but ambulatory and able to
carry out work of a light or sedentary nature, e.g., light housework, office
work.
2 Ambulatory and capable of all self-care but unable to carry out any work
activities. Up and about more than 50% of waking hours.
3 Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
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4 Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
An ECOG performance status will also be assessed on Lead-in Day 1 (Phase lb).
The
ECOG performance status assessed at Screening will serve as the baseline for
clinical
assessment.
12-Lead Electrocardiogram (ECG) (Phase 1)
A 12-lead resting ECG were performed for all subjects in the first 2 cohorts
at Screening,
Cycle 1 Day -3, Cycle 1 Day 14, Day 1 of each subsequent cycle and at the
Final Visit. For
subsequent cohorts, an ECG were performed at Screening, Cycle 1 Day -3 and Day
14,
Cycle 3 Day 1 and Day 14 and at the Final Visit.
For subjects enrolled in Phase lb, Eggs will be performed at Screening, Cycle
1 Day 1,
Cycle 1 Day 14, Cycle 3 Day 1, Cycle 3 Day 14 and Final Visit. An ECG will
also be
performed on Lead-in Day 1 during the lead-in period. The data were assessed
on an
ongoing basis and ECG monitoring may be adjusted depending on the observation
of any
clinically significant findings.
All ECGs should be taken approximately 6-8 hours post-dose (2-8 hours post-
dose is an
acceptable timeframe), and if possible at approximately the same time of day.
If
pharmacokinetic data indicates the Cmax of parent drug or a major metabolite
occurs at a time
different than this specified range, the timing of the ECG were modified. A
qualified
physician will sign and date the ECGs, determine if any findings outside
normal
physiological variation are clinically significant (in consultation with a
cardiologist, if
necessary) and document this on the appropriate CRF. The original ECG tracing
with
physician assessment were retained in the subject's records at the study site
and a copy were
faxed to the Oncology Group Safety Desk via the contact information. The ECG
measurement obtained at Screening were used to document baseline status of the
subject so
that safety comparisons can be made, if necessary. Repeat ECGs were performed
whenever
clinically necessary.
12-Lead Electrocardiogram (ECG) (Phase 2a)
A 12-lead resting ECG were performed for all subjects in the Phase 2a portion
of the study
at Screening, on Cycle 1 Day 14, Cycle 3 Day 14 and at the Final Visit. All
ECGs should be
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taken approximately 6-8 hours post-dose (2-8 hours post-dose is an acceptable
timeframe),
and at approximately the same time of day. If pharmacokinetic data indicates
the Cmax Of
parent drug or a major metabolite occurs at a time different than this
specified range, the
timing of the ECG may be modified. A qualified physician will sign and date
the ECGs,
determine if any findings outside normal physiological variation are
clinically significant
(in consultation with a cardiologist, if necessary) and document this on the
appropriate CRF.
The original ECG tracing were retained in the subject's records at the study
site and a copy
will be faxed to the Oncology Group Safety Desk via the contact information
provided in
Section 6.5. The ECG measurement obtained at Screening were used to document
baseline
status of the subject so that safety comparisons can be made, if necessary.
Repeat ECGs
were performed whenever clinically necessary.
2D Echocardiogram with Doppler (Phase la and Phase lb)
In Phase la, a 2D echocardiogram with Doppler were performed for all subjects
in the first
2 cohorts at Screening, Cycle 1 Day -3 and Day 14, Day 1 of each subsequent
cycle and at
the Final Visit. For subsequent cohorts in Phase 1 a, an echocardiogram with
Doppler were
performed at Screening, Cycle 1 Day -3 and Day 14, Cycle 3 Day 1 and Day 14
and at the
Final Visit. For subjects enrolled in Phase lb, an echocardiogram with Doppler
will be
performed at Screening, Cycle 1 Day 1, Cycle 1 Day 14, Cycle 3 Day 1 Cycle 3
Day 14 and
Final Visit. An echocardiogram will be performed on Lead-in Day 1 during the
lead-in
period.
If necessary, the Cycle 1 Day 14 and Cycle 3 Day 14 echocardiograms may be
performed
within 3 days prior to Day 14. An echocardiogram will also be performed on
Lead-in Day 1
during the lead-in period. The test results were assessed on an ongoing basis
and monitoring
may be adjusted depending on the observation of any clinically significant
findings.
All echocardiograms should be taken approximately 6-8 hours post-dose (2-8
hours post-
dose is an acceptable timeframe), and if possible at approximately the same
time of day. If
pharmacokinetic data indicates the Cmax of parent drug or a major metabolite
occurs at a time
different than this specified range, the timing of the echocardiogram were
modified. A
qualified physician will sign and date the echocardiogram reports, determine
if any findings
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outside normal physiological variation are clinically significant and document
this on the
appropriate CRF. The original echocardiogram report with physician assessment
were
retained in the subject's records at the study site and a copy were faxed to
the Oncology
Group Safety Desk via the contact information provided in Section 6.5. In
addition, Abbott
will require access to the recording of the echocardiogram as necessary. The
echocardiogram results obtained at Screening were used to document baseline
status of the
subject so that safety comparisons can be made, if necessary. Repeat
echocardiograms were
performed whenever clinically necessary.
Bone Marrow Biopsy
A bone marrow biopsy were performed for all subjects at Screening (within 21
days prior to
the first does of study drug) to determine disease involvement in the marrow
and for
pharmacodynamic analysis.
Bone marrow biopsy for pharmacodynamic analysis is described in Section 5.3.7.
The bone
marrow biopsy at Screening should be performed after all other eligibility
criteria have been
met, unless otherwise obtained through standard of care. For subjects with
bone marrow
involvement at study entry, a repeat bone marrow biopsy should be obtained if
the subject's
best response to ABT-263 is determined to be a Complete Response (CR). This
should be
performed within 8-12 weeks after criteria (CR) are first met.
Bone Marrow Aspirate and Biopsy for NCI-WG criteria
A bone marrow biopsy will be performed at Screening (within 21 days prior to
the first dose
of study drug) unless a bone marrow aspirate and biopsy was obtained within 12
weeks of
staring study drug without intervening treatment and is representative of the
subject's
existing CLL. The bone marrow aspirate and biopsy should be performed after
all eligibility
criteria have been met, unless otherwise obtained through standard of care.
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If a subject meets all the clinical and laboratory criteria for a complete
response (CR)(except
for platelet counts due to potential drug related toxicity), a bone marrow
aspirate and biopsy
should be performed 3 months after the criteria are first met in order to
confirm a CR.
Bone marrow aspirates and biopsies performed as standard of care throughout
the study
should also be captured on a case report form.
Tumor Assessments for IWG criteria
Computed Tomography (CT) of involved anatomic regions, magnetic resonance
imaging
(MRI, if medically indicated) and bone marrow biopsy (if medically indicated)
were used in
evaluation of all subjects using the IWG criteria for tumor response at
Screening, at the end
of Cycle 2 and Cycle 4, every 3rd cycle thereafter and at the Final Visit.
Subjects will
continue to be monitored by the same methods unless evidence of tumor
metastasis warrants
otherwise. The tumor assessment performed at Screening will serve as the
baseline for
clinical assessment. Response criteria definitions are outlined in Section
5.3.3.1.
A PET scan using fluorodeoxyglucose (FDG) will be used to differentiate
between an
unconfirmed complete response (Cru) and complete response (CR) for subjects
enrolled in
Phase 2a with diffuse large B-cell lymphoma (Arm Q. The following IWG criteria
for
complete response will be used for this population:
o Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or
when
the PET scan positive before therapy a post-treatment residual mass of any
size is
permitted as long as it is PET negative.
o Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a
pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph
nodes
and nodal masses must have regressed on CT to normal size (less than or equal
to 1.5
cm their greatest diameter for nodes > 1.5 cm before therapy). Previously
involved
nodes that were 1.1-1.5 cm in their long axis and more than 1.0 cm in their
short axis
before treatment must have decreased to < 1.0 cm in their short axis after
treatment.
Subjects will continue to be monitored by the same methods unless evidence of
tumor
metastasis warrants otherwise. The tumor assessment performed at Screening
will serve as
the baseline for clinical assessment.
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Tumor assessments for NCI-WG Criteria
Analysis of peripheral blood, physical examination, bone marrow aspirate and
biopsy, CT
scan of involved anatomical regions and MRI (if medically indicated) will be
used.
Subjects will be evaluated against the NCI-WG criteria2l (physical
examination/CT/MRI)
at the end of Cycle 2, the end of Cycle 4, the end of every 3rd cycle
thereafter, and at the
Final Visit. Analysis of peripheral blood will be evaluated against the NCI-WG
criteria
for tumor response assessment on Day 1 (pre-dose) of the following cycle. For
example,
when a subject completes Cycle 2, the laboratory values from Day 1 of Cycle 3
(pre-dose) will be used to assess tumor response.
A CT scan of involved anatomic regions (or MRI, if medically indicated) will
be done at
Screening (within 21 days prior to the first dose of study drug). The tumor
assessment
performed at Screening will serve as the baseline for clinical assessment.
If a subject meets all the clinical and laboratory criteria for a complete
response (CR) or a
partial response (PR) (except for platelet counts due to potential drug
related toxicity), a
CT scan should be performed 3 months or 2 months respectively, after the
criteria are
first met in order to confirm a CR or PR.
CT scans and MRIs performed as standard of care throughout the study should
also be
captured on a case report form.
Pregnancy Test
For female subjects of childbearing potential, the local reference laboratory
will perform a
serum pregnancy test at Screening and a urine pregnancy test before dosing on
Cycle 1 Day
-3 (Phase 1) or Cycle 1 Day 1 (Phase 2a). The test results must be reviewed
and determined
to be negative prior to dosing.
Subjects considered not of childbearing potential must be documented as being
surgically
sterile or post-menopausal (for at least one year).
Clinical Laboratory Tests
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In Phase la and Phase lb, local laboratories will be utilized to process and
provide results
for the clinical laboratory tests. The principal investigator or
subinvestigator will review,
initial and date all laboratory results. The laboratory test results will be
collected on the
Case Report Forms.
All laboratory measurements obtained through Day 1 of Cycle 2 in Phase 1 a and
Phase lb, will be faxed to the Oncology Group Safety Desk within 24 hours via
the
contact information provided in Section 6.5.
Phase la
Hematology, chemistry, and urinalysis will be collected at:
= Screening
= Cycle 1 Day -3
= Cycle 1 Day 1, Day 2 and Day 3 (chemistry and hematology only)
= Weekly through Cycle 2
= Day 1 of subsequent Cycles (or within 72 hours)
= Final Visit
= Safety Follow-up Visit Hematology, chemistry and urinalysis samples were
collected at
Screening, Cycle 1 Day -3 (Phase 1) or Cycle 1 Day 1 (Phase 2a), Cycle 1 Day 2
(Phase 1)
or Cycle 1 Day 3 (Phase 2a) (chemistry and hematology only), weekly through
the first 2
cycles, Day 1 of each subsequent cycle (or within 72 hours prior), at Final
Visit and at the
Safety Follow-up Visit. Results must be available and reviewed prior to
dosing. The
laboratory test results from Screening (except platelet count) will serve as
the baseline for
clinical assessment.
= Chemistry tests should be obtained under fasting conditions if possible.
= Triglycerides will only be collected at Screening and at the Final Visit.
= Local laboratories were utilized to process and provide results for the
clinical
laboratory tests. The principal investigator or subinvestigator will review,
initial
and date all laboratory results. The laboratory test results were collected on
the
Case Report Forms.
Table 6. Clinical Laboratory Tests
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Hematology Clinical Chemistry Urinalysis
Hematocrit Blood urea nitrogen (BUN) Specific gravity
Hemoglobin Creatinine Ketones
Red blood cell (RBC) count Total bilirubin pH
White blood cell (WBC) Serum glutamic-pyruvic Protein
count
Neutrophils transaminase (SGPT/ALT) Blood
Bands Serum glutamic-oxaloacetic Glucose
Lymphocytes transaminase (SGOT/AST)
Monocytes Alkaline phosphatase Microscopic
examination
Basophils Sodium (as indicated)
Eosinophils Potassium
Platelet count (estimate not Calcium
acceptable) Inorganic phosphorus
Prothrombin time (PT) Uric acid
Activated partial
thromboplastin Cholesterol
time (aPTT) Total protein
Mean platelet volume Glucose
(MPV)
Mean corpuscular Triglycerides (Screening and Final
hemoglobin
(MCH) Visit)
Mean corpuscular volume Albumin
(MCV)
Mean corpuscular Lactate dehydrogenase (LDH)
hemoglobin
concentration (MCHC) Magnesium
Reticulocyte count Chloride
Bicarbonate
mylase (Screening, CID14 and
Final Visit)
ipase (Screening, CID 14 and Final
Visit)
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For any laboratory test value outside the reference range that the
investigator considers to be
clinically significant:
= The investigator may repeat the test to verify the out-of-range value.
= The investigator will follow the out-of-range value to a satisfactory
clinical
resolution.
= A laboratory test value that requires a subject to be discontinued from the
study were recorded as an adverse event.
Phase 2a
Clinical laboratory samples obtained in Phase 2a will be assessed using a
certified central
laboratory (Quest Diagnostics). This data will be used for all data analysis.
The central
laboratory for this study will provide instructions regarding the collection,
processing and
shipping of these samples. All laboratory samples should be shipped to the
central laboratory.
Phase 2a
Clinical laboratory samples obtained in Phase 2a will be assessed using a
certified central
laboratory (Quest Diagnostics). This data will be used for all data analysis.
The central
laboratory for this study will provide instructions regarding the collection,
processing and
shipping of these samples. All laboratory samples should be shipped to the
central laboratory.
Hematology, chemistry, and urinalysis will be collected at:
= Screening
= Cycle 1 Day 1
= Cycle 1 Day 2 and Day 3 (chemistry and hematology only)
= Weekly through Cycle 2
= Day 1 of subsequent Cycles (or within 72 hours)
= Final Visit
= Safety Follow-up Visit
For subjects who are at high risk for tumor lysis syndrome during Cycle 2 and
beyond,
additional hematology and chemistry samples may be collected as per the
management
guidelines in Section 6.7.5.
A certified local reference laboratory may perform hematology and chemistry
tests for
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immediate subject management; however split or concurrent samples must be
drawn and
sent to the central laboratory for analysis.
Local laboratories will be utilized to process and provide results for all
platelet counts.
Platelet count results must be available and reviewed prior to dosing. The
laboratory test
results from Screening (except platelet count) will serve as the baseline for
clinical
assessment.
Table 9. Clinical Laboratory Tests
Hematology
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Prothrombin time (PT)
Activated partial thromboplastin
time (aPTT)
Mean platelet volume (MPV)
Mean corpuscular hemoglobin
(MCH)
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin
concentration (MCHC)
Reticulocyte count
Clinical chemistry (a,b)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
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Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Amylase (Screening,
C1D14 and Final Visit)
Lipase (Screening, C1D14
and Final Visit)
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination
(as indicated)
a. Chemistry tests should be obtained under fasting conditions if possible.
b. Triglycerides will only be performed at Screening and Final Visit.
For any laboratory test value outside the reference range that the
investigator considers to
be clinically significant:
= The investigator may repeat the test to verify the out-of-range value.
= The investigator will follow the out-of-range value to a satisfactory
clinical
resolution.
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= A laboratory test value that requires a subject to be discontinued from the
study will be recorded as an adverse event.
Assignment of Subiect Numbers
For the Phase 1 portion of the study, the results of all screening and pre-
dose Study Day 1
(or Lead-in Day 1 for lead-in period) evaluations must be within clinically
acceptable
limits, upon review by the investigator with the concurrence of the Abbott
Medical Monitor
or designee, before a subject can be administered study drug. Subjects will
not be enrolled in
the study if laboratory or other screening results are not within clinically
acceptable limits.
Subjects who meet the inclusion criteria and do not meet any of the exclusion
criteria were
assigned a unique subject number.
The results of all screening and pre-dose Study Day 1 evaluations must be
within
clinically acceptable limits (per inclusion criteria in Section 5.2.1), upon
review by the
investigator before a subject can be administered study drug. Subjects will
not be
enrolled in the study if laboratory or other screening results are not within
clinically
acceptable limits. Subjects who meet the inclusion criteria and do not meet
any of the
exclusion criteria will be assigned a unique subject number by Abbott, as
described in
Section 5.5.3.
Meals and Dietary Requirements
For the first cycle in the Phase 1 study, ABT-263 were administered to all
subjects under
fasting conditions on Day -3 and non-fasting conditions on Days 1 through 14.
Subjects may
not consume grapefruit or grapefruit products within the 3-day period prior to
initial drug
administration and until the last treatment cycle is completed due to possible
CYP3A-
mediated metabolic interaction. On Day -3, subjects will not be allowed to
take food or
beverage, except for water to quench thirst, from 8 hours prior to dosing
until after the
collection of the 4-hour blood sample. No fluids except those required for
dosing were
allowed for 1 hour before dosing and 1 hour after dosing. On Days 1 and 14,
all subjects will
have a standard breakfast at study sites prior to administration of ABT-263.
The meal
content will consist of approximately 520 Kcal; with approximately 30%
calories from fat.
Blood Samples for Pharmacogenetic Analyses
DNA
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One 4 mL whole blood sample for DNA isolation were collected at Screening from
each
subject who consents to provide samples for pharmacogenetic analysis.
The samples were collected into EDTA tubes and stored under frozen conditions
until
shipment on dry ice to Abbott.
If pharmacogenetic testing is performed, results from individual subjects were
kept coded
and confidential. Abbott will store the DNA samples in a secure storage space
with adequate
measures to protect confidentiality. Samples were coded so that subject
identities will not be
available to the scientists conducting the genotyping analysis.
Specimens for Pharmacodynamic Analyses
Blood Collection for Proteomics
Approximately 6 mL of blood were collected by venipuncture into one 6-mL EDTA
(purple
cap) tube at Screening, Cycle 1 Day 14, Cycle 2 Day 14, and at the Final Visit
from all
subjects. The collection should be performed as described below. The complete
process of
centrifugation, transfer to cryovial and freezing should be accomplished in
less than 1 hour
from blood draw.
= Collect the blood samples into a 6-mL EDTA (purple top) tube.
= Immediately invert the collection tube 8-10 times (so clot formation is
reduced).
= Centrifuge sample at 1200-1500 X g for 15 minutes at 2-8 C.
= Within 15 minutes, transfer the plasma into a separate 4 ML labeled cryovial
and freeze at -70 C.
= Store samples at -70 C until shipped to Abbott on dry ice sufficient for
three days.
Specimens for Pharmacodynamic Analyses
Phase la and Phase lb Pharmacodynamic Collections
Mandatory Collections
= Proteomics
= Bone marrow aspirate for tumor cells. If a bone marrow aspirate is not
collected, a bone marrow core biopsy may be obtained
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Optional Collections
= DNA sample
= Formalin fixed, paraffin embedded archived diagnostic tissue for IHC and
FISH analysis
= Core needle biopsies (two are preferred)
o One core needle biopsy that is formalin-fixed for IHC and FISH analysis
o One core needle biopsy that is flash frozen for CGH/microarray analysis
Phase 2a Pharmacodynamic Collections
Mandatory Collections
= One of the following is required for all subjects in the Phase 2a portion of
the
study:
o Core needle biopsy of malignant lymph node.
o Bone marrow aspirate or core positive for lymphoma.
o Archived tumor tissue with no intervening treatment since the biopsy
(e.g., from debulking, tissue obtained at relapse or bone marrow sample).
= Proteomics
Optional Collections
= DNA sample
If none of the above is attainable for a potential subject (Phase 1 a, Phase l
b, and
Phase 2a), the Abbott Medical Monitor should be contacted.
Needle biopsies will also be obtained at time of relapse from all subjects in
the Phase 2a
portion of the study.
Processing of Pharmacodynamic Specimens
Blood Collection for Proteomics
Approximately 6 mL of blood will be collected by venipuncture into one 6-mL
EDTA
(purple cap) tube at Screening, Cycle 1 Day 14, Cycle 2 Day 14, and at the
Final Visit
from all subjects. The collection should be performed as described below. The
complete
process of centrifugation, transfer to cryovial and freezing should be
accomplished in less
than 1 hour from blood draw.
= Collect the blood samples into a 6-mL EDTA (purple top) tube.
= Immediately invert the collection tube 8-10 times (so clot formation is
reduced).
= Centrifuge sample at 1200-1500 x g for 15 minutes at 2-8 C.
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= Within 15 minutes, transfer the plasma into a separate 4 mL labeled cryovial
and freeze at -70 C.
= Store samples at -70 C until shipped to Abbott on dry ice sufficient for
three
days.
Tissue Collection for IHC and FISH Fixed Samples
Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were
performed
on tissue slides from archived, diagnostic, formalin fixed, paraffin embedded
(FFPE) tissue
blocks from all subjects who consent in the Phase 1 portion of the study and
from all
subjects in the Phase 2a portion of the study.
From each representative FFPE block, the local pathology laboratory should
prepare
slices of tissue with a thickness of approximately 4-6 microns and apply to
positively
charged slides to be used for IHC and FISH analysis. Therefore, a minimum of
(15) 4-6
microns of tissue sections should be collected from each subject block. In
cases where there
is not enough appropriate tissue available to provide these sections, the
investigator will
15 communicate with the pathology laboratory to determine the maximum number
of slides that
can be provided, and relay that information to Abbott prior to slide
preparation.
To ensure optimal sampling, two quality control slides must also be prepared
by the
pathology laboratory and included in the shipment of slides to Abbott. These
quality control
slides were representative of the beginning and of the end of the tissue
section. These slides
are to be stained using Hematoxylin and Eosin (H&E) and reviewed by the local
pathologist
to ensure the diagnostic quality of viable tumor and normal cells (i.e., large
regions of
necrosis or areas composed primarily of fibrous connective tissue or adipose
tissue are not
the predominant feature). The remaining tissue prepared for the unstained
slides were
procured from the sections closest to the section that is of adequate
diagnostic quality.
Included with each shipment should be a copy of the pathology report and
completed
shipment inventory form. Tissue slides were shipped in slide boxes. Slide
boxes should be
packaged using suitable shipping materials and sent to Abbott at ambient
temperature.
Needle Biopsies Phase 1
Needle biopsies were obtained prior to therapy and at time of relapse, when
feasible, for all
subjects in the Phase 1 portion of the study who consent and who have readily
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tumor tissue. Biopsies were performed after consent, prior to drug
administration and after
the subject has relapsed on therapy.
Phase 2a
One of the following is required for all subjects in the Phase 2a portion of
the study:
= Core needle biopsy of malignant lymph node obtained at Screening.
= Bone marrow aspirate or core obtained at Screening, positive for lymphoma.
= Archived tumor tissue with no intervening treatment since the biopsy (e.g.,
from
debulking, tissue obtained at relapse or bone marrow sample).
If none of the above is attainable for a potential subject, the Abbott Medical
Monitor should
be contacted.
Needle biopsies will also be obtained at time of relapse from all subjects in
the Phase 2a
portion of the study.
It is preferred that at least two core biopsies be obtained. These biopsies
should be at least
18 gauge in diameter and at least 1 cm in length. It is estimated that there
were between 2-5
million cells from each biopsy. The biopsies may be processed according to the
institutional
standard procedures or per the following instructions. If a procedure other
than what is
described below is used, a description of the procedure should be provided to
Abbott.
One core biopsy is to be fixed in formalin for between 8-24 hours then
embedded in paraffin
and stored at -20 C until shipment to Abbott at ambient temperature. The
second core
biopsy specimen should be placed into properly labeled cryovial. The tumor
sample were
flash frozen in liquid nitrogen immediately after collection. The specimen
were stored
frozen at -70 C until shipment to Abbott. Samples should be shipped to Abbott
on dry ice
sufficient for 3 days.
Bone Marrow Collection Bone Marrow Aspirate
Bone marrow aspirates should be drawn at baseline in conjunction with the
diagnostic
biopsy. The aspirate may be processed according to the institutional standard
procedures or
per the following instructions. If a procedure other than what is described
below is used, a
description of the procedure should be provided to Abbott.
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Fresh fixative solution should be prepared by adding 8 mL of concentrated
fixative in tube A
to tube B, which contains 32 mL of diluent (both tubes were provided and
wrapped in foil),
and mixed 5-6 times. Approximately 2 mL of bone marrow aspirate should be
diluted in 2
mL of phosphate buffered saline (PBS), then pipetted up and down (titurated) 5-
6 times with
a 10 mL pipette to create a single cell suspension. This 4 mL suspension
should be added to
the prepared fixative, mixed 5-6 times and the samples should be placed in a -
70 C freezer
until shipment to Abbott.
Bone Marrow Core Biopsy
If bone marrow aspirate is not collected, a bone marrow core biopsy may be
obtained. The
core may be processed according to the institutional standard procedures or
per the
following instructions. If a procedure other than what is described below is
used, a
description of the procedure should be provided to Abbott.
The core should be fixed in freshly prepared 4% paraformaldehyde. A 10 mL
ampule of
20% paraformaldehyde and a 50 mL conical tube (tube C) containing 40 mLs of 1X
PBS
were provided. The paraformaldehyde from the ampule should be added to tube C,
mixed 4-
5 times and then the core bone marrow biopsy should be added. The sample
should be
allowed to fix for 16-24 hours at 4 C and then embedded in paraffin.
Table 7. Phase 1 Schedule of Biomarker Sample Collection
Cycle 1 Day Cycle 2 Day
Screening 14 14 Off Treatment
DNA 4 mL blood'
Proteomics 6 mL blood 6 mL blood 6 mL blood 6 mL blood
CGH/microarray Core needle biopsy-flash Core needle
frozen' iopsy-flash
frozen (time of
elapse)'
IHC/FISH = Archived diagnostic Core needle
FFPE tissue' iopsy formalin-
ixed (time of
= Core needle biopsy
elanse)'
Tumor Cellsa 2 mL bone marrow
aspirate
a. Bone marrow aspirate samples for analysis should be obtained with the bone
marrow biopsies (for disease status).
20b. Optional collection.
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Table 8. Phase 2a Schedule of Biomarker Sample Collection
Cycle 1 Day Cycle 2 Day
Screening 14 14 Off Treatment
DNA 4 mL blood'
Proteomics 6 mL blood 6 mL blood 6 mL blood 6 mL blood
CGH/microarray Core needle biopsy-flash Core needle
frozen iopsy-flash
frozen (time of
elapse)
IHC/FISH = Archived diagnostic Core needle
FFPE tissue biopsy formalin-
= Core needle biopsy fixed (time of
formalin-fixed elapse)
Tumor Cellsa
2 mL bone marrow
aspirate
a. Bone marrow aspirate samples for analysis should be obtained with the bone
marrow biopsies (for disease
status).
b. Optional collection.
Drug Concentration Measurements
Collection of Samples for Analysis
Blood Samples for ABT-263 Assay
For Phase 1, blood samples for ABT-263 assay were collected by venipuncture
into 3-mL
evacuated potassium EDTA-containing collection tubes during Cycle 1 at the
following
times: Day -3, prior to dosing (0 hour) and at 0.5, 1, 2, 3, 4, 6, 8, 24, 48
and 72 (Day 1, pre-
dose sample) hours after dosing; Day 1, at 0.5, 1, 2, 3, 4, 6, 8 and 24 (Day
2, pre-dose
sample) hours after dosing; Day 14, prior to dosing (0 hour) and at 0.5, 1, 2,
3, 4, 6, 8 hours
after dosing. Additional blood samples were collected at 0 hour (pre dose) on
Day 14, Cycle
2 through Cycle 6. Sufficient blood were collected to provide approximately 1
mL plasma
from each sample. A total of 27 blood samples (approximately 81 mL) were
collected per
subject for pharmacokinetic analysis during Cycle 1 and one additional blood
sample per
subject per cycle in the following cycles (up to Cycle 6).
For Phase 2a, blood samples (-3 mL) were collected pre-dose (0 hour) and 4
hours post-
dose on Cycle 1 Day 14 only.
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Blood and plasma samples must be protected from direct sunlight during
collection,
processing and storage. Immediately after collection, the blood samples were
inverted
several times to ensure good mixing of the blood and anticoagulant, and were
placed in an
ice bath.
The timing of blood collections will take priority over all other scheduled
study activities
except for dosing. The order of blood collections were maintained to the
minute such that
the time intervals relative to the preceding dosing were the same for all
subjects. The time
that each blood sample is collected were recorded to the nearest minute.
Urine Samples for ABT-263 Assay (Phase 1)
Urine for ABT-263 assay were collected in containers without preservatives 0
to 24 hours
after dosing on Cycle 1 Day -3 only from the subjects who participate in the
Phase 1 dose
escalation study. Subjects were instructed to void immediately prior to dosing
and one 3 mL
aliquot were retained for baseline drug assay (pre-dose sample). Thereafter,
urine were
collected 0-24 hours following dosing. The start and stop times of the
collection interval
were recorded to the nearest minute. All urine collected during a collection
interval were
kept refrigerated until the end of the interval. To ensure complete urine
collection, subjects
were instructed to void into a container at the conclusion of the collection
interval.
Handling/Processing of Samples
Blood Samples for ABT-263 Assay
The blood samples for ABT-263 assay were centrifuged within 1 hour of
collection at 1200-
1500 X g for 15 minutes using a refrigerated centrifuge (2-8 C) to separate
the plasma. The
plasma samples were transferred using plastic pipettes into screw-capped
polypropylene
tubes labeled with the drug number name, type of sample (plasma), the protocol
number, the
subject number, the study cycle and day and the planned time of sampling
relative to dosing.
The plasma samples were frozen at -20 C or colder within 1 hour after
collection and will
remain frozen until shipped.
Urine Samples for ABT-263 Assay
All urine collected over the specified time interval were thoroughly mixed and
the volume
were measured and recorded. One 3 mL aliquot were placed in a screw-capped
polypropylene tube labeled with the drug number name, type of sample (urine),
the protocol
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number, the subject number, the study cycle and day and the planned collection
interval. The
urine samples were frozen at -20 C until shipped.
Efficacy Variables
All efficacy analyses are exploratory in nature. The exploratory efficacy
endpoints include
tumor response (determined using IWG Criteria), progression free survival
(PFS), time to
tumor progression (TTP), overall survival (OS), duration of overall response
and ECOG
performance status.
IWG Criteria for Tumor Response
Only subjects with measurable disease are eligible for the Phase 2a study.
Changes in the
measurable lesions over the course of therapy were evaluated using the IWG
criteria listed
below.
Eligibility
Only subjects with measurable disease at baseline can have objective tumor
response
evaluated as an endpoint.
Measurable Disease The presence of at least one measurable lesion. If the
measurable disease is restricted to a solitary lesion,
its neoplastic nature should be confirmed
b y cytology/histology.
Measurable Lesions Lesions that can be accurately measured in at least one
dimension with longest diameter > 10 mm.
All measurements should be taken and recorded in metric notation using a ruler
or calipers.
All baseline evaluations should be performed as closely as possible to the
beginning of
treatment and never more than four weeks before the beginning of the
treatment.
The same method of assessment and the same technique should be used to
characterize each
identified and reported lesion at baseline and during follow-up.
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Clinical lesions will only be considered measurable when they are superficial
(e.g., skin
nodules and palpable lymph nodes). For the case of skin lesions, documentation
by color
photography including a ruler to estimate the size of the lesion is required.
Methods of Measurement
CT is the preferred method to measure lesions selected for response
assessment. MRI may
be used if medically indicated (e.g., severe contrast allergy). Conventional
CT and MRI
should be performed with cuts of 7 mm or less in slice thickness contiguously.
Spiral CT
should be performed using a 5 mm contiguous reconstruction algorithm. This
applies to
tumors of the chest, abdomen and pelvis.
Lesions on chest x-ray are acceptable as measurable lesions when they are
clearly defined
and surrounded by aerated lung; however, CT is preferable.
For accurate objective response evaluation, ultrasound (US) should not be used
to measure
tumor lesions. However, US is a possible alternative to clinical measurements
of superficial
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also
be useful to
confirm the complete disappearance of superficial lesions usually assessed by
clinical
examination.
Cytology and histology can be used to differentiate between partial response
(PR) and
complete response (CR) in rare cases (e.g., after treatment to differentiate
between residual
benign lesions and residual malignant lesions in tumor types such as germ cell
tumors).
Assessment of response were performed by the investigator and documented on
the
appropriate CRF page.
Complete Response (CR) requires the following:
1. Complete disappearance of all detectable clinical and radiographic evidence
of
disease and disappearance of all disease-related symptoms if present before
therapy,
and normalization of lymphoma related biochemical abnormalities.
2. All lymph nodes and nodal masses must have regressed to normal size (< 1.5
cm in their
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously
involved
nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before
treatment must
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have decreased to < 1 cm in their greatest transverse diameter after
treatment, or by
more than 75% in the sum of the products of the greatest diameters (SPD).
3. The spleen, if considered to be enlarged before therapy on the basis of a
CT scan,
must have regressed in size and must not be palpable on physical examination.
4. For subjects with disease in the bone marrow, tumor infiltrate must be
cleared on
repeat bone marrow aspirate and biopsy of the same site. The sample on which
this
determination is made must be adequate (> 20 mm biopsy core).
Complete Response/Unconfirmed (CRu):
1. CR/unconfirmed (CRu) includes those patients who fulfill criteria 1 and 3
above,
but with one or more of the following features:
2. A residual lymph node mass greater than 1.5 cm in greatest transverse
diameter
that has regressed by more than 75% in the SPD. Individual nodes that were
previously
confluent must have regressed by more than 75% in their SPD compared with the
size
of the original mass.
3. Indeterminate bone marrow (increased number or size of aggregates without
cytologic or
architectural atypia).
Partial Response (PR) requires the following:
1. A > 50% decrease in SPD of the six largest nodes or nodal masses. These
nodes
or masses should be selected according to the following features: (a) they
should be
clearly measurable in at least two perpendicular dimensions, (b) they should
be from
as disparate regions of the body as possible, and (c) they should include
mediastinal
and retroperitoneal areas of disease whenever these sites are involved.
2. No increase in the size of the other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by at least 50% in the SPD.
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4. With the exception of splenic and hepatic nodules, involvement of other
organs is
considered assessable and not measurable disease.
5. Bone marrow assessment is irrelevant for determination of a PR because it
is
assessable and not measurable disease; however, if positive, the cell type
should be
specified in the report, e.g., large-cell lymphoma or low-grade lymphoma
(i.e., small,
lymphocytic small cleaved, or mixed small and large cells).
6. No new sites of disease. Stable Disease (SDI
Stable disease is defined as less than a PR (see above) but is not progressive
disease (see
below).
Progressive Disease (PD) requires the following (for PR, nonresponders):
1. A > 50% increase from nadir in the SPD of any previously identified
abnormal
node for PRs or nonresponders.
2. Appearance of any new lesion during or at the end of therapy.
Relapsed Disease requires the following (for CR, CRu):
1. Appearance of any new lesion or increase by - 50% in the size of previously
involved
sites.
2. - 50% increase in greatest diameter of any previously identified node
greater than 1
cm in its short axis or in the SPD of more than one node.
A summary of the criteria described above is shown below.
Physical Lymph Node Bone
Response Category Examination Lymph Nodes Masses Marrow
CR Normal Normal Normal Normal
CRu Normal Normal Normal Indeterminate
Normal Normal > 75% Normal or
decrease indeterminate
PR Normal Normal Normal Positive
Normal -50% -50% Irrelevant
Decrease in -50% -50% Irrelevant
liver/spleen decrease decrease
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Relapse/progressio Enlarging New or New or Reappearance
n liver/spleen; new increased increased
sites
Note: See text for definitions of "normal" and "indeterminate."
Confirmation
The goal of confirmation of objective response is to avoid overestimating
responses. In
cases where confirmation of response is not feasible, it should be made clear
when reporting
the outcome that the response(s) is (are) not confirmed.
To be assigned a status of PR, CR or CRu changes in tumor measurements must be
confirmed by repeat assessments that should be performed within 4-8 weeks
after the criteria
for response are first met.
In the case of SD, follow-up measurements must have met the SD criteria at
least once after
study entry at a minimum interval, not less than 6 weeks following initiation
of treatment.
5.3.5 Pharmacokinetic Variables
Values for the pharmacokinetic parameters of ABT-263, including the maximum
observed
plasma concentration (Cmax), the time to cmax (peak time, Tmax), the terminal
phase elimination
rate constant (f3), terminal elimination half-life (tl/2), the area under the
plasma
concentration-time curve (AUC) from time 0 to the time of the last measurable
concentration (AUCt) and from time 0 to infinite time (AUCoc) for the doses on
Cycle 1 Day
-3, Cycle 1 Day 1 and Cycle 1 Day 14 in Phase 1, whenever applicable, were
determined
using noncompartmental methods. The percent of dose recovered in urine as ABT-
263
(%Ae) and renal clearance (CLR) were determined if there is meaningful amount
of ABT-
263 recovered in urine. Additional parameters may be calculated if useful in
the
interpretation of the data.
5.3.6 Pharmacogenetic Variables
DNA samples may be analyzed for genetic factors contributing to the subject's
response to
ABT-263 in terms of pharmacokinetics and safety. The samples may also be used
for the
development of a diagnostic test for such a drug response. Based on
observations in rats and
the projection of human PK, phase II enzymes, Bcl-2 family members and
intestinal
transporters may be of primary interest. Genetic studies in general may
include
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determination of the relationship of genetic haplotypes and drug metabolism,
transport,
therapeutic response and adverse events. The samples may also be used for the
development
of a diagnostic test for drug response.
Pharmacodynamic Variables
Several putative biomarkers of efficacy and response were evaluated in this
protocol with
the goal of defining the relationship between drug concentration and disease
status.
Examination of the proteomic profiles of subjects on the ABT-263 clinical
trials may reveal
patterns of protein/peptide concentrations that may be further evaluated in
future clinical
studies to determine any prognostic value and any correlation with clinical
response.
Samples were analyzed for predictive or drug-responsive proteomic markers. In
the event
that any plasma samples are unused, remaining samples were anonymized and
banked for
use in diagnostic test development efforts.
Tissue slides from diagnostic biopsies were used for immunohistochemistry
(IHC) and
fluorescence in situ hybridization (FISH). Immunohistochemical analysis were
performed on
tissue slides from archived, diagnostic tissue blocks and banked for use in
diagnostic test
development efforts. Given the targeted nature of ABT-263 for a subset of anti-
apoptotic
proteins (Bcl-2, Bcl-XL, and Bcl-w), the relationship between sensitivity of
cell lines to
ABT-263 and the expression levels of the Bcl-2 family members has been
examined in
human tumor cell lines. Bcl-2 expression levels (mRNA and protein) exhibited
strong
correlations with sensitivity, and the protein concentrations of Bcl-XL
paralleled that of Bcl-
2. Conversely, higher expression levels (mRNA and protein) of Mcl-1 was
associated with
resistance. Taken together, preclinical data suggests that tumor cells
sensitive to ABT-263
will exhibit high Bcl-2 and Bcl-XL expression coupled to low Mcl-1 expression
whereas the
inverse were reflective of ABT-263 resistance. Consequently, pre- and post-
treatment
subject tumor specimens obtained from diagnostic biopsies (with no treatment
intervention)
or fixed core needle biopsies and/or bone marrow aspirates/core biopsies were
evaluated for
relative expression of the Bcl-2 family members. Moreover, an additional pre-
and post-
treatment biopsy were flash frozen for genetic analysis, which may include
expression
microarray to assess gene expression and/or CGH to assess global gene
amplifications and
deletions.
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Amplification of 1 8q2 1, containing the Bcl-2 gene locus, has been observed
in SCLC cell
lines having the highest sensitivity to ABT-263 and represents a potential
genetic lesion
associated with drug sensitivity. Fluorescent in-situ Hybridization (FISH)
were conducted
on tissue from archived tumor samples from subjects participating in this
study to assess
amplifications and translocations in the Bcl-2 gene and other family member
genes which
may prove to be informative. The potential relationship between amplification
of these
genes and the clinical outcome in these patients were examined as a subjects
stratification
tool. Biospecimens collected during the course of this study may be banked and
used in the
future to investigate new scientific questions related to this study.
Treatments Administered
Subjects self-administered ABT-263 orally once daily (QD). Each dose were
taken with
approximately 240 mL of water. On days that pre-dose pharmacokinetic sampling
is
required (Cycle 1 Day -3, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 14, Cycle
2 Day 14,
Cycle 3 Day 14, Cycle 4 Day 14, Cycle 5 Day 14 and Cycle 6 Day 14 in Phase 1
and on
Cycle 1 Day 14 in Phase 2a) dosing will occur in the morning in the clinic to
facilitate
pharmacokinetic sampling. In Phase 1, all subjects will receive ABT-263 under
fasting
conditions (after an 8-hour fast and 4 hours before lunch) on Cycle 1 Day -3
and
at 30 minutes after the start of a standard breakfast on Cycle 1 Day 1. On all
other dosing
days of Phase 1, the subjects will receive ABT-263 at approximately 30 minutes
after
breakfast. In Phase 2a, all subjects will self-administer ABT-263 at
approximately 30
minutes after breakfast. The effect of food on pharmacokinetics were evaluated
and changes
were initiated if fasting conditions are superior.
On extensive PK collection days (Cycle 1 Day -3, Cycle 1 Day 1 and Cycle 1 Day
14 of
Phase 1), the time of each drug administration were recorded to the nearest
minute. On all
other days, subjects were instructed to record the date and time they take
their study drug.
Subject diaries were provided by Abbott.
Identity of Investigational Products
Study Drug
Formulation
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Powder for Oral
Solution (2.0
ABT-263 grams/bottle base
equivalent,
25 mg/mL when
mixed)
* N/A = Not Applicable
Diluents for Constitution
= Phosal 53 Medium Chain Triglyceride (MCT), 120 grams/bottle.
= Alcohol (Ethanol), Dehydrated, USP/EP/JP 200 Proof.
Phase 1/2a Study Pharmacokinetics
=ABT-263 exposure is dose-proportional
- Mean AUC: 47 pg = h/mL at 225 mg (n=4); 100 pg = h/mL at 315 mg (n=5); 109
pg h/mL at 440
mg (n=3)
- Preclinical target AUC: 53 to 88 pg = h/mL=ABT-263 peak concentration (Cmax)
-8 hours post-dose
=Half-life -14-20 hours
=Peak-to-trough plasma concentration ratio -3 fold at steady state
-Inter-subject variability in exposure -40%
=Food has mild positive effect on ABT-263 oral absorption
Additional data shown in attached figures.
The foregoing is meant to illustrate the invention but not to limit it.
Variations and
changes obvious to one skilled in the art are intended to be within the scope
of the invention
as defined in the appended claims.
42
SUBSTITUTE SHEET (RULE 26)
